: Acute kidney injury (AKI) - defined by rapid and often complete loss of the kidney's excretory function - is a common life-threatening complication in diverse clinical settings including sepsis, hypovolemia, cardiac surgery, and kidney transplantation. Nearly 2% of all people hospitalized in the United States each year suffer from AKI. Their mortality rate can be as high as 80% and patients who survive AKI have longer hospitalizations and nearly an 8% chance of needing long-term dialysis. The financial cost of AKI in the United States is enormous - estimated to be $10 billion annually. There is no specific therapy to prevent AKI, to hasten its recovery, or to abrogate its side effects partly because the pathogenesis of AKI is not fully understood. It is recognized that whatever its cause, AKI is accompanied by inflammation. However, it is not known what components of inflammation are causes versus what components are consequences of kidney damage and it is not known if inflammation regulates the injury process. By seeking answers to these questions we can address this knowledge gap and drive the AKI field forward. Our long-term goal is to identify and map causal pathways of inflammation in AKI and harness this knowledge to develop specific therapies for AKI. The objective of the current application is to establish that C-reactive protein (CRP) steers leukocytes towards a pathway of inflammatory destruction during AKI. Our central hypothesis is that during AKI, CRP conducts the orchestrated actions of dendritic cells, neutrophils, monocytes, and macrophages in an Fc R- dependent fashion that worsens tissue injury and hampers its repair. This central hypothesis was formulated based on published observations made in the clinic and in vitro and preliminary data that we generated using CRP transgenic and CRP knockout mice, all indicating that CRP exacerbates AKI. The rationale for our research is that by establishing CRP causality we will elevate this protein from the status of biomarker of inflammation to new therapeutic target for AKI, which is sorely needed. We will test our central hypothesis by pursuing 4 specific aims. Aim 1 is to identify CRP-responsive leukocytes that contribute to AKI: The hypothesis being that CRP modifies dendritic cell, neutrophil, monocyte, and macrophage actions in ways that worsen AKI and hamper the kidney repair process. Aim 2 is to determine how CRP elicits injurious leukocyte responses in AKI: The hypothesis is that CRP triggered modification of leukocyte actions depends on CRP binding to Fc receptors. Aim 3 is to ascertain the source of injurious CRP: The hypothesis is that CRP expressed in the liver (not the kidney) is what exacerbates injury. Aim 4 is to assess the efficacy of CRP targeting in AKI: The hypothesis is that pharmacologic lowering of CRP will lessen AKI severity. These working hypotheses will be tested by subjecting CRP transgenic mice versus their counterparts lacking specific leukocyte populations or Fc Rs, to experimentally induced AKI. Efficacy of a novel CRP lowering drug will be tested. The project's success will establish how CRP initiates, drives, and modifies AKI and reveal a potential new therapy for AKI.